Cyclic oxyguanidine pyrazinones as protease inhibitors

Abstract

Cyclic oxyguanidine pyrazinone compounds are described, including compounds of the Formula I: wherein R 3 , R 4 , R 5 , W, and A are as set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. Compositions for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation are described. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

1 - 29 . (canceled)  
   
   
       30 . A compound of formula:  
     
       
         
         
             
             
         
       
     
     or a salt thereof; wherein: 
 R a , R b  and R c  are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO 2 R W , where R W  is alkyl, cycloalkyl, phenyl, benzyl,  
                     
 where R d  and R e  are independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl or phenyl, R f  is hydrogen, C 1-6  alky, C 2-6  alkenyl or phenyl, R g  is hydrogen, C 1-6  alkyl, C 2-6  alkenyl or phenyl, and R h  is aralkyl or C 1-6  alkyl;  
 each n is from zero to 4;  
 each m is from zero to 4; and  
 each j is from zero to 4; provided that n, m and j are not all zero; and  
 P a  is hydrogen or benzyloxycarbonyl.  
 
   
   
       31 . A compound of  claim 30 , wherein R a , R b  and R c  are independently one of hydrogen, C 1-6  alkyl, hydroxy, C 1-6  alkoxy, cyano, or —CO 2 R W  where R w , in each instance, is C 1-4  alkyl or C 4 - 7  cycloalkyl.  
   
   
       32 . A compound of  claim 31 , wherein R a , R b  and R c  are independently one of hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, —CO 2 CH 3 , —CO 2 CH 2 CH 3  or —CO 2 CH 2 CH 2 CH 3 .  
   
   
       33 . A compound of  claim 32 , wherein R a , R b  and R c  are each hydrogen.  
   
   
       34 . A compound of  claim 31 , wherein R a , R b  and R c  are independently —CO 2 R W , where R w  is one of  
     
       
         
         
             
             
         
       
     
     where R d —R h  are defined as in  claim 30 .  
   
   
       35 . A compound of  claim 34 , wherein 
 R d , R e  and R g  are each hydrogen;    R f  is methyl; and    R h  is benzyl or tert-butyl    
   
   
       36 . A compound of  claim 30 , wherein P a  is hydrogen.  
   
   
       37 . A compound of  claim 30 , wherein 
 each n is zero, 1, or 2;    each m is zero, 1, or 2; and    each j is zero, 1, or 2; provided that n, m and j are not all zero.    
   
   
       38 . A compound of  claim 37 , wherein n is zero, m is 1, and j is 1.  
   
   
       39 . A compound of formula:  
     
       
         
         
             
             
         
       
     
     or a salt thereof; wherein: 
 R a , R b  and R c  are independently hydrogen, alkyl, hydroxyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO 2 R w , where  
 R w  is alkyl, cycloalkyl, phenyl, benzyl,  
                     
 where R d  and R e  are independently hydrogen, c 1-6  alkyl, C 2-6    
 alkenyl or phenyl, R f  is hydrogen, C 1-6  alkyl, C 2-6  alkenyl or  
 phenyl, R g  is hydrogen, C 1-6  alkyl, C 2-6  alkenyl or phenyl, and R h  is aralkyl or C 1-6  alkyl;  
 each n is from zero to 4;  
 each m is from zero to 4; and  
 each j is from zero to 4; provided that n, m and j are not all zero; and  
 P a  is hydrogen or benzyloxycarbonyl.  
 
   
   
       40 . A compound of  claim 39 , wherein R a , R b  and R c  are independently one of hydrogen, C 1-6  alkyl, hydroxy, C 1-6  alkoxy, cyano, or —CO 2 R W  where R w , in each instance, is C 1-4  alkyl or C 4 - 7  cycloalkyl.  
   
   
       41 . A compound of  claim 40 , wherein R a , R b  and R c  are independently one of hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy, cyano, —CO 2 CH 3 , —CO 2 CH 2 CH 3  or —CO 2 CH 2 CH 2 CH 3 .  
   
   
       42 . A compound of  claim 41 , wherein R a , R b  and R c  are each hydrogen.  
   
   
       43 . A compound of  claim 40 , wherein R a , R b  and R c  are independently —CO 2 R W , where R w  is one of  
     
       
         
         
             
             
         
       
     
     where R d —R h  are defined as in  claim 39 .  
   
   
       44 . A compound of  claim 43 , wherein 
 R d , R e  and R g  are each hydrogen;    R f  is methyl; and    R h  is benzyl or tert-butyl    
   
   
       45 . A compound of  claim 39 , wherein P a  is benzyloxycarbonyl.  
   
   
       46 . A compound of  claim 39 , wherein 
 each n is zero, 1, or 2;    each m is zero. 1, or 2; and    each j is zero, 1, or 2; provided that n, m and j are not all zero.    
   
   
       47 . A compound of  claim 46 , wherein n is zero or 1, m is 0, and j is 1.  
   
   
       48 . A process for preparing a compound of Formula I:  
     
       
         
         
             
             
         
       
     
     or a hydrate or pharmaceutically acceptable salt thereof; wherein: 
 W is hydrogen, R 1 , R 1 OCO, R 1 CO, R 1 (CH 2 ) g NHCO, or (R 1 ) 2 CH(CH 2 ) g NHCO, wherein s is 0-4;  
 R 1  is 
 R 2 ,  
 R 2 (CH 2 ) t C(R 12 ) 2 , where t is 0-3, and each R 12  can be the same or different,  
 (R 2 )(OR 12 )CH(CH 2 ) p , where p is 1-4, 
 (R 2 ) 2 (OR 12 )C(CH 2 ) p , where p is 1-4,  
 
 R 2 C(R 12 ) 2 (CH 2 ) t , wherein t is 0-3, and each R 12  can be the same or different, wherein (R 12 ) 2  can also form a ring with C represented by C 3-7 cycloalkyl,  
 R 2 CF 2 C(R 12 ) 2 (CH 2 ) q , wherein q is 0-2, and each R 12  can be the same or different, wherein (R 12 ) 2  can also form a ring with C represented by C 3-7 cycloalkyl,  
 R 2 CH 2 C(R 12 ) 2 (CH 2 ) q , wherein q is 0-2, and each R 12  can be the same or different, wherein (R 12 ) 2  can also form a ring with C represented by C 3-7 cycloalkyl,  
 (R 2 ) 2 CH(CH 2 ) r , where r is 0-4 and each R 2  can be the same or different, and wherein (R 2 ) 2  can also form a ring with CH represented by C 3-7  cycloalkyl, C 7-12  bicylic alkyl, C 10-16  tricylic alkyl, or a 5- to 7-membered mono- or 9- or 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,  
 R 2 O(CH 2 ) p , wherein p is 2-4,  
 (R 2 ) 2 CF(CH 2 ) r , wherein r is 0-4 and each R 12  can be the same different, wherein (R 12 ) 2  can also form a ring with C represented by C 3-7  cycloalkyl, C 7-12  bicyclic alkyl, C 10-16  tricyclic alkyl, or a 5- to 7-membered mono- or 9- or 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,  
                     
 where s is 0 or 1, or  
 R 2 CF 2 C(R 12 ) 2 ;  
 
 R 2  is 
 phenyl, naphthyl, or biphenyl, each of which is unsubstituted or substituted with one or more of C 1-4  alkyl, C 1-4  alkoxy, halogen, hydroxy, CF 3 , OCF 3 , COOH, CONH 2 , or SO 2 NH 2 ,  
 a 5- to 7-membered mono- or a 9- to 10-membered bicyclic heterocyclic ring or non-heterocyclic ring which can be saturated or unsaturated, wherein the heterocyclic ring is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl, each of which is optionally substituted with halogen or hydroxy, and wherein the heterocyclic or non-heterocyclic ring is unsubstituted or substituted with halogen or hydroxy,  
 C 1-7 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, aryl, C 3-7 cycloalkyl, CF 3 , N(CH 3 ) 2 , —C 1-3 alkylaryl,  
 CF 3 ,  
 C 3-7 cycloalkyl, unsubstituted or substituted with aryl,  
 C 7-12 bicyclic alkyl, or  
 C 10-16  tricyclic alkyl;  
 
 R 3  is 
 hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted C 6-10 aryl, optionally substituted C 6-10 ar(C 1-6 )alkyl, trifluoromethyl, halogen, C 1-6 hydroxyalkyl, cyano, nitro, carboxamido, —CO 2 R x , —CH 2 OR x  or —OR x , where R x , in each instance, is independently one of hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;  
 
 R 4  is 
 hydrogen or halogen;  
 
 R 12  is 
 hydrogen,  
 phenyl, naphthyl, or biphenyl, each of which is unsubstituted or substituted with one or more of C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxy, CF 3 , OCF 3 , COOH, or CONH 2 ,  
 a 5- to 7-membered mono- or 9- to 10-membered bicyclic heterocyclic ring which is selected from the group consisting of piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl,  
 C 1-4 alkyl, unsubstituted or substituted with one or more of hydroxy, COOH, amino, or aryl,  
 CF 3 ,  
 C 3-7 cycloalkyl,  
 C 7-12 bicyclic alkyl, or  
 C 10-16 tricyclic alkyl;  
 
 R 5  is hydrogen, C 1-4 alkyl, or C 2-4 alkenyl;  
 A is one of  
                     
 R a , R b  and R c  are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO 2 R w , where  
 R w  is alkyl, cycloalkyl, phenyl, benzyl,  
                     
 where R d  and R e  are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl or phenyl, R f  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or phenyl, R g  is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or phenyl, and R h  is aralkyl or C 1-6 alkyl;  
 each n is from zero to 4;  
 each m is from zero to 4; and  
 each j is from zero to 4; provided that n, m and j are not all zero;  
 comprising condensing or coupling a compound of formula:  
                     
 or a salt thereof, with a compound of Formula II:  
                     
 where W, R 3 , R 4 , R 5 , R a , R b , R c , n, m and j are as defined above.